Only recently has it become evident that distal excitatory synapses are different from proximal excitatory synapses in the hippocampus, and that these differences confer to distal synapses the same influence on neuronal output as their more proximal counterparts. Similarly, it has been shown only recently that Diochemical processing related to Alzheimer's disease (AD) targets synapses and affects the number of AMPA receptors (AMPARs) bound to their postsynaptic membrane. The proposed research will examine the mechanisms of distance-dependent synaptic scaling and their vulnerability to AD-like biochemical processing using a multi-disciplinary analysis of synapses in a mouse model of AD (the 5XFAD transgenic line) and their nontransgenic littermate controls. The central goal of this proposal is assist the Principal Investigator establish his independence and secure a tenure-track faculty position such that he can lead a major research program aimed at understanding the interplay among synapses, behavior, and disease. The Mentored Phase of this proposal will provide the applicant with training in serial section postembedding immunogold electron microscopy and whole-cell patch-clamp physiology from two experts in their fields: Dr. Yuri Geinisman and Dr. Nelson Spruston, respectively. Such multidisciplinary training will facilitate the applicant's transition to independence by enabling him to design, perform, and interpret experiments at multiple, complementary levels of analysis. In the Mentored Phase, the applicant will determine whether synapses in distal regions of the CA1 pyramidal neuron dendrites are stronger than those in more proximal regions, and whether the AD-linked genetic mutations in 5XFAD mice disrupt this distance-dependent regulation of synaptic strength. During the Independent Phase, the applicant will combine his training in electron microscopy and whole-cell patch-clamp physiology to determine whether the number, size, and plasticity in synapses throughout the dendritic axis of CA1 pyramidal neurons are regulated within single dendrites in control mice, and whether these parameters are dysregulated as a consequence of A? overproduction in 5XFAD mice. Together, the proposed experiments will help identify the contributions of synaptic subtypes to location-independent synaptic communication in hippocampal neurons, while simultaneously determining whether synapses are targeted by AD, and whether some synaptic subtypes are more at risk than others. This proposal takes advantage of the collaborative environment at Northwestern University and includes training at various light and electron microscopy workshops, laboratory-based training in cellular physiology, journal clubs, mouse genotyping, and computer programming. In addition, the training environment will provide numerous opportunities for career development through national research presentations, collaborations, mentoring students, and training on the responsible conduct of research.